Asymmetric induction in stereoselective carbocyclization of cyclohexanone enamines

Article abstract of DOI:10.1055/s-1999-2569

A highly enantioselective synthesis of bicyclo[3.3.1 ]nonane diketones 3-5 was accomplished by (S)- and (R)-2-methoxymethylpyrrolidine induced asymmetric cyclization of cyclohexanone enamines 1,2 in reaction with propenoyl chloride. A possible enantiodifferentiation reaction mechanism was suggested.

Full text of DOI:10.1055/s-1999-2569

234
LETTER
Asymmetric Induction in Stereoselective Carbocyclization of Cyclohexanone
Enamines
Eugenius Butkus , Arvydas StonËius
Department of Organic chemistry, Vilnius university, Naugarduko 24, 2006 Vilnius, Lithuania
Fax + 370 2-630987; E-mail: eugenijus.butkus@chf.vu.lt
Received 28 September 1998
Abstract:
A
highly enantioselective synthesis of bicyc-
lo[3.3.1]nonane diketones 3-5 was accomplished by (S)- and (R)-2-
methoxymethylpyrrolidine induced asymmetric cyclization of cy-
clohexanone enamines 1,2 in reaction with propenoyl chloride. A
possible enantiodifferentiation reaction mechanism was suggested.
Key words: enamine cyclization, SMMP/RMMP asymmetric in-
duction, bicyclo[3.3.1]nonanediones
Asymmetric induction has gained a very broad range of
applications both in development of principles of asym-
metric synthesis and practical applications.1 (S)-2-Meth-
oxymethylpyrrolidine ((S)-MMP) is a pioneer chiral
auxiliary in chiral syntheses due to the fact that this re-
agent is relatively cheap and good asymmetric inductions
are reached.2 Synthesis using (S)-MMP enamines is one
of the most powerful methods of asymmetric reactions
though only a few cyclizations have been reported by
Seebach and co-workers.3 We wish to report here higly
enantioselective carbocyclization reactions of (S)-and
(R)-MMP cyclohexanone enamines with propenoyl chlo-
ride suggesting also a possible enantiodifferentiation
mechanism. The reaction of cyclohexanone enamines
with α,β-unsaturated acid chlorides has been shown
to give racemates of chiral bicyclo[3.3.1]nonane struc-
ture,4a-c which is a key skeleton in hispidospermidin, hu-
perzine A, sesquiterpenes trifarienols A and B, and some
other natural and biologically valuable products.5 There-
fore the enantioselective carbocycle construction is im-
portant for the production of a variety of structural
analogues of this framework.
The diastereomeric and enantiomeric purity of the reac-
tion products were analysed by chiral GLC, NMR and
measurement of specific rotation angle. GLC analysis us-
ing a stationary phase modified with β-cyclodextrin of a
reaction product of enamine (S)-1 showed that (-)-bicyc-
lo[3.3.1]nonane-2,9-dione (70% ee) was the main prod-
uct.8 A comparison of the specific rotation angle with an
authentic sample obtained earlier by a semipreparative
HPLC separation of the corresponding racemic mixture9
and spectra proved that the product was the (1R,5S)-enan-
tiomer 3a. Using (R)-enamine the (1S,5R)-enantiomer 3b
was obtained with a higher enantiomeric excess (Table 2).
Enantiomeric 7-methyl-bicyclo[3.3.1]nonane-2,9-diones
4,5 were formed in the reaction of methylcyclohexanone
enamines 2. The main product was exo-methyl bicyclic
diketone 4a (diastereomeric excess 98% after purifica-
tion).
The exo-configuration of the methyl group was proved by
a GLC and NMR comparison with the racemic sample ob-
tained by a cyclization of the morpholine enamine with
propenoyl chloride.10 The minor diastereomer was not
isolated from the reaction mixture. It is interesting to note
that, again, the cyclization reaction of (R)-2 enamine gave
almost exclusively (+)-exo-diketone 4b and also with
higher ee compared to (S)-enamine. The asymmetric cy-
clization reaction results are presented in Scheme 1 and
summarized in Table 2.
The chiral enamines 1 and 2 were prepared from cyclo-
hexanone and 4-methylcyclohexanone and (S)- or (R)-2-
MMP under standard conditions6 (TsOH, benzene, Dean-
Stark trap) in an atmosphere of nitrogen to avoid addition
of oxygen to the pyrrolidine enamines. Carbocyclization
of the enamines was effected by a slow addition of a pro-
penoyl (acryloyl) chloride solution in benzene to a boiling
solution of enamine in benzene.7 The conditions were
similar to the reaction of morpholine enamines with α,β-
unsaturated acid chlorides which has led to the carbocy-
clization.4 However, since the MMP enamines were less
reactive the optimum reaction conditions had to be estab-
lished. It was found that the yield of the cyclization prod-
uct increased at prolonged reaction time and lower
concentration of enamine in a reaction mixture (Table 1).
Three possible mechanisms of cyclization between enam-
ines and a,b-unsaturated acid chlorides should be consid-
ered according to the literature data 4c,11: 1. N-acylation of
enamine and following [3,3] sigmatropic rearrangement
leading to a highly reactive ketene participating in further
cyclization, 2. Michael addition with subsequent cycliza-
tion - C-acylation and 3. a direct C-acylation following
Michael addition. No obvious conclusion could be made
from the previous investigations as to which one of the
three mechanisms is occurring. It is also known that
Synlett 1999, No. 2, 234–236 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Induction in Stereoselective Carbocyclization of Cyclohexanone Enamines
235
ride is shown in Scheme 2. The dipolar intermediate A
involved in enamine Michael addition is stabilized by in-
tramolecular solvation of the suitably oriented meth-
oxymethyl group (cf. 13). This stabilization is indicated by
the dashed lines between a cationic nitrogen, a methoxy
group oxygen, and a negatively charged oxygen in (S)-A
intermediate (Scheme 2).
Scheme 2
In the case where the reaction follows any other of the
mentioned pathways the methoxymethyl group could
cause only some steric restrictions for reagent approach to
the double bond of the enamine. Consequently, the chiral
center formed during the first addition would have the op-
posite configuration and the enantiomeric purity of the ob-
tained product would be low. The enantiomeric purity of
bicyclo[3.3.1]nonane-2,9-diones 3a,b synthesized in this
work was ≥80%. The configuration of the first formed
chiral center is in agreement with the stereochemical
course of the Michael addition. The asymmetric cycliza-
tion reactions of chiral MMP and 4-methylcyclohexanone
enamines were also highly diastereoselective. The exo-7-
methylbicyclo[3.3.1]nonane-2,9-dione 4a is the main di-
astereomer formed in both asymmetric and ordinary syn-
theses. This indicates that both reactions proceeded
according to the same mechanism.
Scheme 1
Michael addition of activated olefins to chiral 2-(meth-
oxymethyl)pyrrolydine enamines is highly stereoselec-
tive.12
The above suggests that the Michael addition in the first
step is dominating in cyclizations of MMP enamines with
propenoyl chloride.
The stereochemical course of this reaction is controlled by
the stereoelectronic effects, and the orientation of the
methoxymethyl group is of significant importance to ste-
reodifferentiation. Michael addition of propenoyl chloride
to (S)-2-(methoxymethyl)pyrrolydine enamines occurs
strictly from the heterotopic Re-face. Thus, the chiral cen-
ter formed in a reaction of SMMP enamine has the (S)-
configuration. On the contrary, addition to (R)-2-MMP
enamines occurs from the Si-face and leads to the (R)-con-
figuration of the chiral center. The reaction course in the
case of cyclohexanone and (S)-2-(methoxymethyl)pyrro-
lydine enamine cyclization reaction with propenoyl chlo-
In summary, a highly enantioselective and diastereoselec-
tive synthesis of bicyclononane ketones via enamine cy-
clization reaction has been developed. The compounds
have potential in the assembly of natural product skele-
tons.
Acknowledgement
We thank the Lithuanian Science and Studies Foundation for the fi-
nancial support. We are grateful to Dr. U. Berg and Prof. T. Frejd
for providing chiral GC facilities at Lund University.
Synlett 1999, No. 2, 234–236 ISSN 0936-5214 © Thieme Stuttgart · New York

236
E. Butkus, A. StonËius
LETTER
(7) Enamine cyclization, typical experimental procedure: To a
boiling solution of 0.01 mol enamine (S)-1 in 20 ml of anhy-
drous benzene under nitrogen a solution of 0.01 mol prop-
enoyl chloride in 10 ml anhydrous benzene was added over
2.5 h. Reaction mixture was heated at 130-140°C for 5 h. The
mixture was cooled and the yellow precipitate was filtered off,
washed with hexane, and hydrolysed with ice-cooled water
overnight. Extractive workup with dichloromethane and di-
stillation of the solvent gave a solid residue which was puri-
fied by sublimation at 90°C/2mm Hg. (1R,5S)-(-)-3a: [α]D -
67.8° (c 0.005 CHCl3). GLC: tR 9.93 min 150°C/4°C·min-1/
230°C. (1S,5R)-(+)-3b, [α]D +78.5° (c 0.005 CHCl3). GLC: tR
9.92 min., 150°C/4°C·min-1 /230°C. 1H NMR (D2O) δ 1.25-
2.57 (m, 8H, 4 H2C), 2.62-2.78 (m, 3H, HC, H2C-C=O), 3.06-
3.13 (m, 1H, HC(-C=O)2). (1R,5R,7R)-(-)-4a m.p. 47-48°C
(from pentane-hexane); [α]D -19.1° (c 0.0048 CHCl3); GLC:
tR 12.34 min. 150°C/2°C·min-1/190°C; (1S,5S,7S)-(+)-4b m.p.
50-51oC (from pentane-hexane); [α]D+20.0° (c 0.0055
CHCl3). 1H NMR δ 0.92 (d, 3H, H3C, J 6Hz) 1.5-2.9 (m, 10H),
3.06 (m, H1, HC(-C=O)2); MS m/z (rel. intensity) 166 (89%,
M+.), 151 (11%), 138 (9%), 124 (60%), 110 (43%), 95 (64%),
82 (29%), 77 (8%), 67 (33%), 55 (100%), 41 (18%); endo-5,
tR 14,63 min.; MS m/z 166 (88%, M+.), 151 (17%), 137 (4%),
124 (67%), 110 (41%), 96 (58%), 82 (26%), 77 (9%), 67
(30%), 55 (100%), 41 (20%).
References and Notes
(1) Mander, L.N. In Eliel, E.L.; Wilen, S.H. Stereochemistry of
Organic Compounds, Wiley: New York, 1994, 835-990, and
references cited therein.
(2) Enders, D.; Klatt, M. Synthesis 1996, 1403-1418.
(3) (a) Seebach, D.; Inwinkelried, R.; Weber, T. “EPC (enantio-
merically pure compound) syntheses with carbon-carbon
bond formations via acetals and enamines”, in Modern Syn-
thetic Methods, Scheffold, R. Ed., Springer-Verlag : Berlin,
1986, 4, 217-240. (b) Seebach, D.; Missbach M., Calderari G.,
Eberle M. J. Am. Chem. Soc. 1990, 112, 7625-7638.
(4) Hickmott, P.W.; Hargreaves, J.R. Tetrahedron 1967, 23,
3151-3159; (b) Butkus, E.; Bielinyte, B. J. Prakt. Chem./
Chem.-Ztg. 1992, 334, 285-287. (c) Butkus, E.; Bielinyte-Wil-
liams, B. Collect. Czech. Chem. Commun. 1995, 60, 1343 -
1356. (d) Audia, J.E.; Lawhorn, D.E.; Deeter, J.B. Tetrahe-
dron Lett. 1993, 34, 7001-7004. (e) Barta, N.S.; Brode, A.;
Stille, J.R. J. Am. Chem. Soc. 1995, 116, 6201-6206.
(5) (a) Huang, H.; Forsyth, C.J. J. Org. Chem. 1995, 60, 5746-
5747. (b) Kakiuchi, K.; Horiguchi, T.; Minato, K.; Tobe, Y.;
Kurosawa, H. J. Org. Chem. 1995, 60, 6557-6562. (c) Kocar,
M.; Bersz, B. Tetrahedron 1987, 43, 2129-2134. (d) Snatzke,
G.; Kinsky, K. Tetrahedron 1972, 28, 295-301. (e) Xia, Y.;
Kozikowski, A.P. J. Am. Chem. Soc. 1989, 111, 4116-4117.
(f) Frontier, A.J.; Raghavan, S.; Danishefsky S.J. J. Am.
Chem. Soc. 1997, 119, 6686-6687.
(6) Synthesis of enamines, typical experimental procedure:
0.026 mol of (S)-(+)-2-(methoxymethyl)pyrrolidine, 0.053
mol of cyclohexanone or 4-methyl cyclohexanone and a cata-
lytic amount of p-toluenesulfonic acid in 35 ml of anhydrous
benzene was refluxed under nitrogen using a Dean-Stark trap
for 4-6 h. Benzene was evaporated and the residue distilled in
vacuo under nitrogen. (2S)-1-(4-methylcyclohexen-1-yl)-2-
(methoxymethyl)pyrrrolidine (S)-1 b.p. 139-141°C/13mm
Hg; (R)-1, b.p. 99-101°C/0.5 mm Hg. 1H NMR (C6D6) δ 0.87-
2.45 (m, 12H, H2C), 2.6-3.8 (m, 5H, H2C-O, H2C-N, HC-N),
3.5 (s, 3H, H3C-O), 4.5 (s, 1H, HC=). (S)-2, b.p. 116-117°C/4
mm Hg; (R)-2, b.p. 111-113°C/1 mm Hg. 1H NMR (CDCl3) δ
0.8-2.5 (m, 11H), 1.1 (d, 3H, H3C-C, J 6.4Hz), 2.8-3.85 (m,
5H, H2C-N, H2C-O, HC-N), 3.4 (s, 3H, H3C-O), 4.3 (s, 1H,
HC=C).
(8) The ee was determined on a Perkin Elmer Autosystem gas
chromatograph using 30m×25mm Alpha-Dex 120 or Beta-
Dex 120 capillary columns (Supelco), carrier gas He (6.0 bar),
split injector (1:100), flame ionisation detection.
(9) Berg, U.; Butkus, E. J. Chem. Res.(S) 1993, 116-117.
(10) StonËius, A. PhD thesis, Vilnius university, 1998.
(11) Hickmott, P.W.; Miles, G.J.; Sheppard, G.; Urbani, R.;
Yoxall, Ch. T.; J. Chem. Soc., Perkin Trans. 1 1973, 1514-
1519.
(12) (a) Oare, D.A.; Heathcock, C.H. Topics Stereochem. 1991, 20,
87-120. (b) Blarer, S.J.; Schweizer, W. B.; Seebach, D. Helv.
Chim. Acta 1982, 65, 1637-1654.
(13) Blarer, S.J.; Seebach, D. Chem. Ber. 1983, 116, 2250-2260.
Synlett 1999, No. 2, 234–236 ISSN 0936-5214 © Thieme Stuttgart · New York